The present disclosure relates to compounds, compositions, and methods for treating glucagon-like peptide-1 receptor related diseases and/or disorders, such as type 2 diabetes, obesity, depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, cognitive dysfunction, learning disability, and asthma.
Type 2 diabetes is a prevalent metabolic disorder characterized by relative insulin deficiency, insulin resistance, and hyperglycemia. Pathologically, pancreatic β cells found in the Islets of Langerhans become progressively dysfunctional and unable to keep up with the demand for increased insulin secretion in the setting of insulin resistance. Ultimately β cells become highly metabolically stressed, and undergo apoptotic cell death, leading to progressively worsening dysglycemia. Concomitant with β cell dysfunction, a cell dysfunction also occurs in diabetes. In this case, the α cells overproduce glucagon, which causes the liver to overproduce glucose, leading to fasting hyperglycemia. The α cells in diabetes no longer respond to normal cues to suppress glucagon production. Obesity is frequently co-morbid with diabetes, and is an important cause of the insulin resistance and is a major risk factor for diabetes. Chronic hyperglycemia and hyperlipidemia contributes to microvascular complications such as neuropathy, retinopathy, nephropathy, and macrovascular disease, such as coronary artery disease and stroke.
Glucagon-like peptide-1 (GLP-1) is synthesized and processed in enteroendocrine L cells in the gut and is released into the local circulation upon nutrient ingestion. It has numerous salutary effects throughout the body by activating its group B G-protein coupled receptor (GPCR). GLP-1 receptors (GLP1R) are expressed in pancreatic β cells where GLP-1 action substantially amplifies insulin secretion, also known as the “incretin effect.” Glucagon over-secretion is an increasingly recognized pathophysiological feature of diabetes, and GLP-1 via GLP1R suppresses glucagon release from α cells. GLP-1 does not increase insulin secretion under euglycemic conditions, nor does it suppress glucagon secretion under hypoglycemic conditions. Thus, diabetes therapeutics that capitalize on the GLP-1 axis have a low risk of hypoglycemia and a significant safety advantage.
A number of effects can be attributed to GLP-1 action in peripheral tissues other than the pancreas and in the CNS. These include effects on CNS control of peripheral glucose homeostasis, lipid metabolism, neuroprotection (Huntington's, Parkinson's, Alzheimier's, stroke), learning and memory, stress and illness responses. GLP-1 is synthesized in the CNS and functions as a neurotransmitter. GLP1R are widely distributed in the CNS where they mediate these pleotropic effects. They are also found in the mediobasal hypothalamus, where activation reduces feeding and weight gain.
Because GLP-1 has been implicated in many diseases and/or disorders, targeting the GLP-1 axis has been the subject of much investigation. Several reports have highlighted its link to a variety of diseases, such as Type 2 diabetes, obesity, depression, Alzheimer's, Parkinson's, and Huntington's disease, stroke, cognitive dysfunction, learning disability, and asthma.